Following the discovery that heparan sulfate, but neither chondroitin sulfate nor heparin, activates TLR4 signaling in dendritic cells and macrophages, evidence has been accumulating that heparan sulfate may play a role in the pathogenesis of MPS neurologic and orthopedic disease via TLR4-induced inflammation [56–58]. This evidence concerns the gene TLR4 and mucopolysaccharidosis.